The intervention of NLRP3 inflammasome inhibitor: oridonin against azoxymethane and dextran sulfate sodium–induced colitis-associated colorectal cancer in male BALB/c mice

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Colorectal cancer (CRC) ranks third globally in cancer diagnoses. The dysregulation of the NLRP3 inflammasome is prominently linked to several types of cancers. Oridonin, a principal component of Rabdosia rubescens, exhibits inhibitory activity against NLRP3 and is well-recognized for its diverse pharmacological benefits. However, its role in an animal model of colitis-associated colorectal cancer (CACC) remains unexplored. In the present study, the effectiveness of oridonin was investigated against CACC, developed using azoxymethane (AOM), a tumour initiator, and dextran sulphate sodium (DSS), a tumour promoter, in male BALB/c mice. The two-stage murine model of inflammation-associated cancer was established by administering AOM (10 mg/kg b.w.; i.p., once) followed by DSS (2% w/v) in drinking water (3 cycles, 7 days/cycle). Over a span of 10 weeks, the dose-dependent (2.5, 5, and 10 mg/kg, b.w.; i.p.) effects of oridonin were investigated in BALB/c mice. Oridonin significantly alleviated CACC severity, as evidenced by reduced DAI scores and restored body weight. Moreover, it attenuated surrogate markers of inflammation, including myeloperoxidase, nitrite, plasma LPS, TNF-α, IL-1β, and DNA damage. Histopathological examination revealed diminished tumorigenesis and apoptotic cells, corroborated by reduced Ki-67 and TNF-α, along with increased p53 expression in the colon. Following oridonin treatment, IHC/immunofluorescence analyses demonstrated a significantly reduced expression of the components of NLRP3 inflammasome including NLRP3, ASC-1, and caspase-1. Notably, the high dose of oridonin (10 mg/kg) consistently exhibited significant protective effects against CACC by modulating various molecular targets. Present findings confirmed the potential of oridonin in the protection of colitis-associated colorectal cancer, providing valuable insights into its mechanism of action and clinical significance. Schematic representation of graphical abstract illustrating (A) stage-specific development of AOM/DSS-induced CACC in male BALB/c mice and (B) drug intervention with oridonin, an NLRP3 inflammasome inhibitor for modulation of various disease parameters and attenuation of carcinogenesis and tumour development. (A) A single AOM injection (10 mg/kg; i.p.) was given to initiate colonic tumour formation, followed by cyclic DSS exposure for tumour progression in male BALB/c mice. Chronic inflammation in the colon triggers the activation of the NLRP3 inflammasome, which promotes tumorigenesis through early dysplasia (identified by pre-cancerous lesions), adenoma (benign tumour from glandular tissue), and carcinoma (invasive malignant tumour) stage. Visible tumours were observed in the colon of BALB/c mice after 10 weeks of AOM/DSS exposure. (B) Treatment with oridonin at a dose of 2.5 mg/kg, 5 mg/kg, and 10 mg/kg ameliorated the biochemical and molecular markers of disease severity, inflammation, and tumour progression in BALB/c mice. Intervention with oridonin improved the colonic histoarchitecture in BALB/c.

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